The major cellular phosphatase Protein Phosphatase 2A (PP2A) is regulated by an unconventional but conserved methylation modification on the very carboxy terminus of its catalytic subunit. However, the functional role of this methylation remains incompletely understood. In the current funding period, it was shown that this methylation modification on PP2A is responsive to intracellular methionine and SAM levels. As such, the amino acid methionine and its downstream metabolite SAM are able to promote the methylation of PP2A and thereby influence the activity of the phosphatase against particular substrates in cellular signaling and growth control. This renewal application proposes to comprehensively investigate the in vivo functions of the methylation of PP2A using a combined genetic, chemical, and proteomic approach. It is notable that this modification on PP2A enables it to function as an amino acid-responsive, metabolically-regulated phosphatase which could impact the phosphorylation status of many important signaling proteins in tune with the metabolic state of the cell.

Public Health Relevance

We plan to investigate an important post-translational modification that contributes to the regulation of cellular signaling in response to particular nutrients. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of metabolic strategies utilized by cancer cells to support their proliferation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Melillo, Amanda A
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Pendleton, Kathryn E; Chen, Beibei; Liu, Kuanqing et al. (2017) The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell 169:824-835.e14
Ye, Cunqi; Sutter, Benjamin M; Wang, Yun et al. (2017) A Metabolic Function for Phospholipid and Histone Methylation. Mol Cell 66:180-193.e8
Chen, Jun; Sutter, Benjamin M; Shi, Lei et al. (2017) GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle. Nat Chem Biol 13:1179-1186
Lee, Chien-Der; Tu, Benjamin P (2017) Metabolic influences on RNA biology and translation. Crit Rev Biochem Mol Biol 52:176-184
Walsh, Christopher T; Tu, Benjamin P; Tang, Yi (2017) Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. Chem Rev :
Huang, Zhiguang; Cai, Ling; Tu, Benjamin P (2015) Dietary control of chromatin. Curr Opin Cell Biol 34:69-74
Shi, Lei; Tu, Benjamin P (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33:125-31
Dutchak, Paul A; Laxman, Sunil; Estill, Sandi Jo et al. (2015) Regulation of Hematopoiesis and Methionine Homeostasis by mTORC1 Inhibitor NPRL2. Cell Rep 12:371-9
Lee, Chien-Der; Tu, Benjamin P (2015) Glucose-Regulated Phosphorylation of the PUF Protein Puf3 Regulates the Translational Fate of Its Bound mRNAs and Association with RNA Granules. Cell Rep 11:1638-50
Savir, Yonatan; Tu, Benjamin P; Springer, Michael (2015) Competitive inhibition can linearize dose-response and generate a linear rectifier. Cell Syst 1:238-245

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